Anastasia Ivanova

33 Pages·2015·1.14 MB·Italian

Sequential Parallel Comparison Design
for Trials with High Placebo Response
Anastasia Ivanova
Department of Biostatistics UNC at Chapel Hill
[email protected]
Placebo response
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Increased placebo response over time
Data from 86 major depressive disorder trials submitted
to FDA during 1986 to 2008 (Khin et al., 2011)
+
US trials
- Non US trials
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Diminished treatment effect over time
.
+
US trials
- Non US trials
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Rising placebo response RCTs and failed trials
Undurraga and Baldessarini 2012
Placebo response
• In many studies in depression and schizophrenia
considered by FDA over 12 year period, 1987 through
1999, in which investigational drug could not be
distinguished from placebo also included an active
standard drug that could not be distinguish from
placebo (Laughren, 2001).
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Placebo response
Yellow pills
make the most effective antidepressants, like little
doses of pharmaceutical sunshine
Red pills
can give you a more stimulating kick
More is better
Placebos taken four times a day deliver greater
relief than those taken twice daily.
More $ is better
Waber, RL, Shiv, B, Carmon, Z, Ariely, D (2008). Commercial
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features of placebo and therapeutic efficacy. JAMA 299: 1016-1017.
Partial List of Illnesses Cited as Having Significant Placebo Responses
Organized by FDA Center for Drug Evaluation and Research Review Divisions
Anesthesia, Analgesic and Gastroenterology (cont.) Psychiatry (cont.)
Rheumatology – Nausea – Chronic Fatigue syndrome
– Arthritis – Obesity – Depression
– Pain – Reflux esophagitis – Insomnia
– Psoriatic arthritis – Ulcerative colitis – Panic disorders
– Rheumatic diseases Neurology – Schizophrenia
Anti-viral – Alzheimer’s Disease – Social Phobia
– Herpes simplex – Autism Pulmonary and Allergy
Cardiovascular and Renal – Epilepsy – Allergies
– Heart failure, congestive – Headache – Asthma
– Hypertension – Migraine – Cough
Ear, Nose and Throat – Multiple Sclerosis – Cystic Fibrosis
– Tinnitus – Parkinson’s disease – Food allergy
Gastroenterology – Restless leg syndrome Reproductive and Urologic
– Crohn’s disease Psychiatry – Benign prostatic
– Dyspepsia and gastric – ADHD enlargement
motility – Anxiety disorders – Erectile dysfunction
– Gastric and duodenal – Binge eating disorder – Premenstrual dysphoric
ulcers – Bipolar mania disorder
– GERD – Sexual dysfunction, women
– Irritable bowel syndrome – Vulvar vestibulitis
– Urinary incontinence
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Design options to lower placebo response
Option 1. Parallel single stage design
R
A
N PLACEBO
D
O
M
I DRUG
Z
E
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Option 2: The Placebo Lead-in
R
PLACEBO
A
No
PLACEBO
N
Response
D
O
M
DRUG
I
Z
E
Use placebo lead-in (run-in) to eliminate placebo responders
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